tbuckley/cabot-search huggingface dataset:
Partnering With Patients, Caregivers, and Clinicians to Determine Research Priorities for Concussion
Authors: Martin H. Osmond, Elizabeth Legace, Peter J. Gill, Rhonda Correll, Katherine Cowan, Jennifer E. Dawson, Randene Duncan, Erin Fox, Kanika Gupta, Ash T. Kolstad, Lisa Marie Langevin, Colin Macarthur, Rosemary Macklem, Kinga Olszewska, Nick Reed, Roger Zemek, Mark Bayley, Phil Fait, Isabelle Gagnon, Noah D Silverberg
Journal: JAMA Network Open (2023)

Importance Identifying research priorities of patients with concussion, their caregivers, and their clinicians is important to ensure future concussion research reflects the needs of those who will benefit from the research. Objective To prioritize concussion research questions from the perspectives of patients, caregivers, and clinicians. Design, Setting, and Participants This cross-sectional survey study used the standardized James Lind Alliance priority-setting partnership methods (2 online cross-sectional surveys and 1 virtual consensus workshop using modified Delphi and nominal group techniques). Data were collected between October 1, 2020, and May 26, 2022, from people with lived concussion experience (patients and caregivers) and clinicians who treat concussion throughout Canada. Exposures The first survey collected unanswered questions about concussion that were compiled into summary questions and checked against research evidence to ensure they were unanswered. A second priority-setting survey generated a short list of questions, and 24 participants attended a final priority-setting workshop to decide on the top 10 research questions. Main Outcomes and Measures Top 10 concussion research questions. Results The first survey had 249 respondents (159 [64%] who identified as female; mean [SD] age, 45.1 [16.3] years), including 145 with lived experience and 104 clinicians. A total of 1761 concussion research questions and comments were collected and 1515 (86%) were considered in scope. These were combined into 88 summary questions, of which 5 were considered answered following evidence review, 14 were further combined to form new summary questions, and 10 were removed for being submitted by only 1 or 2 respondents. The 59 unanswered questions were circulated in a second survey, which had 989 respondents (764 [77%] who identified as female; mean [SD] age, 43.0 [4.2] years), including 654 people who identified as having lived experience and 327 who identified as clinicians (excluding 8 who did not record type of participant). This resulted in 17 questions short-listed for the final workshop. The top 10 concussion research questions were decided by consensus at the workshop. The main research question themes focused on early and accurate concussion diagnosis, effective symptom management, and prediction of poor outcomes. Conclusions and Relevance This priority-setting partnership identified the top 10 patient-oriented research questions in concussion. These questions can be used to provide direction to the concussion research community and help prioritize funding for research that matters most to patients living with concussion and those who care for them.
FDA Grants Full Approval to Paxlovid, COVID-19 Antiviral Treatment
Authors: Emily Harris
Journal: JAMA (2023)

Between 2017 and 2021, the estimated annual rate of new HIV infections declined by 12% in the US, from about 36 500 to about 32 100 infections, due in large part to a decrease in incidence among young people aged 13 to 24 years, according to recent Centers for Disease Control and Prevention (CDC) data.Factors including expansion of HIV testing, treatment, and preexposure prophylaxis (PrEP) underlie the trend, the CDC noted in a statement.The greatest improvement was in the percent of people prescribed PrEP, with 17% more people eligible for PrEP receiving the medication in 2021 than 5 years prior.However, due in part to the effects of the COVID-19 pandemic, the current rate of new HIV infections is not on pace to achieve the federal goal of reducing new HIV infections in 2030 by 90% from 2017 numbers.Moreover, substantial racial and ethnic disparities in HIV infections and access to care persist.Although 30% of people eligible for PrEP received it in 2021, for example, only 12% of American Indian or Alaska Native, Asian, Native Hawaiian and other Pacific Islander, and multiracial people; 11% of Black or African American people; and 21% of Hispanic or Latino people who could benefit received a prescription compared with 78% of White people.
Dynamics and survival associations of T cell receptor clusters in patients with pleural mesothelioma treated with immunotherapy
Authors: Aakash P Desai, Farhad Kosari, Maria Disselhorst, Jun Yin, Alireza Agahi, Tobias Peikert, Julia Udell, Sarah H Johnson, James Smadbeck, Stephen Murphy, Giannoula Karagouga, Alexa McCune, Janet Schaefer-Klein, Mitesh J Borad, John Cheville, George Vasmatzis, Paul Baas, Aaron Mansfield
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden and no robust predictors of survival with ICI. Since ICIs enable adaptive antitumor immune responses, we investigated T-cell receptor (TCR) associations with survival in participants from two clinical trials treated with ICI. Methods We included patients with pleural mesothelioma who were treated with nivolumab (NivoMes, NCT02497508 ) or nivolumab and ipilimumab (INITIATE, NCT03048474 ) after first-line therapy. TCR sequencing was performed with the ImmunoSEQ assay in 49 and 39 pretreatment and post-treatment patient peripheral blood mononuclear cell (PBMC) samples. These data were integrated with TCR sequences found in bulk RNAseq data by TRUST4 program in 45 and 35 pretreatment and post-treatment tumor biopsy samples and TCR sequences from over 600 healthy controls. The TCR sequences were clustered into groups of shared antigen specificity using GIANA. Associations of TCR clusters with overall survival were determined by cox proportional hazard analysis. Results We identified 4.2 million and 12 thousand complementarity-determining region 3 (CDR3) sequences from PBMCs and tumors, respectively, in patients treated with ICI. These CDR3 sequences were integrated with 2.1 million publically available CDR3 sequences from healthy controls and clustered. ICI-enhanced T-cell infiltration and expanded T cell diversity in tumors. Cases with TCR clones in the top tertile in the pretreatment tissue or in circulation had significantly better survival than the bottom two tertiles (p&lt;0.04). Furthermore, a high number of shared TCR clones between pretreatment tissue and in circulation was associated with improved survival (p=0.01). To potentially select antitumor clusters, we filtered for clusters that were (1) not found in healthy controls, (2) recurrent in multiple patients with mesothelioma, and (3) more prevalent in post-treatment than pretreatment samples. The detection of two-specific TCR clusters provided significant survival benefit compared with detection of 1 cluster (HR&lt;0.001, p=0.026) or the detection of no TCR clusters (HR=0.10, p=0.002). These two clusters were not found in bulk tissue RNA-seq data and have not been reported in public CDR3 databases. Conclusions We identified two unique TCR clusters that were associated with survival on treatment with ICI in patients with pleural mesothelioma. These clusters may enable approaches for antigen discovery and inform future targets for design of adoptive T cell therapies.
International Perspectives on Modifications to the Surgical Safety Checklist
Authors: Nathan Turley, Meagan Elam, Mary E. Brindle
Journal: JAMA Network Open (2023)

Importance Modification of the World Health Organization’s Surgical Safety Checklist (SSC) is a critical component of its implementation. To facilitate the SSC’s use, it is important to know how surgical teams modify their SSCs, their reasons for making modifications, and the opportunities and challenges teams face in SSC tailoring. Objective To study SSC modifications in high-income hospital settings in 5 countries: Australia, Canada, New Zealand, the United States, and the United Kingdom. Design, Setting, and Participants This qualitative study used semistructured interviews based on the survey used in the quantitative study. Each interviewee was asked a core set of questions and various follow-up questions based on their survey responses. Interviews were conducted from July 2019 to February 2020 in person and online using teleconferencing software. Surgeons, anesthesiologists, nurses, and hospital administrators from the 5 countries were recruited through a survey and snowball sampling. Main Outcomes and Measures Interviewees’ attitudes and perceptions on SSC modifications and their perceived impact on operating rooms. Results A total of 51 surgical team members and hospital administrators from the 5 countries were interviewed (37 [75%] with &amp;amp;gt;10 years of service; 28 [55%] women). There were 15 (29%) surgeons, 13 (26%) nurses, 15 (29%) anesthesiologists, and 8 (16%) health administrators. Five themes emerged concerning the awareness and involvement in SSC modifications; reasons for modifications; types of modifications; the outcomes of modifications; and perceived barriers to SSC modifications. Based on the interviews, some SSCs may go many years without being revisited or modified. SSCs are modified to ensure they address local issues and standards of practice and that they are fit for purpose. Modifications are also made following adverse events to reduce the risk of reoccurrence. Interviewees described adding, moving, and removing elements from their SSCs, which increased their sense of ownership in their SSC and participation in its performance. Some barriers to modification included leadership and the SSC’s inclusion in hospitals’ electronic medical record. Conclusions and Relevance In this qualitative study of surgical team members and administrators, interviewees described addressing contemporary surgical issues through various SSC modifications. The process of SSC modification may improve team cohesion and buy-in in addition to providing opportunities for teams to improve patient safety.
Errors in Figures
Authors: John Fortney
Journal: JAMA Psychiatry (2023)

In addition, there are minor corrections to the statistical findings for some of the other results.There was also an error in the Statistical Analysis section. 1 The term nonresponders is actually people with 2 or fewer encounters.Response refers to a reduction in symptoms, and our tailoring variable for the sequential, multiple-assignment, randomized trial (SMART) design was engagement in care.An independent statistician and data analyst (who found the mistake) replicated all the findings from the original analyses and then reran all the analyses using the correct subscale (including those published in the supplementary materials).Therefore, we have added recognition of these contributions by Brittany Blanchard, PhD, and Morgan Johnson, MS, to the Additional Contributions section.The corrections for these errors affect the Abstract, text of the main article, Table 2, Figure 3, the eTable in Supplement 2, and the Visual Abstract. 1 We have reviewed the article and confirm that there are no additional errors.We apologize to the readers of the journal for any confusion this has caused and appreciate the opportunity to correct the article.
Hierarchically tumor-activated nanoCRISPR-Cas13a facilitates efficient microRNA disruption for multi-pathway-mediated tumor suppression
Authors: Xiaowei Liu, Suleixin Yang, Li Wang, Xinyue Wu, Xinxin Wang, Chunqing Ou, Jin Yang, Linjiang Song, Shiyao Zhou, Qinjie Wu, Changyang Gong
Journal: Theranostics (2023)

Rationale: CRISPR-Cas13a is an efficient tool for robust RNA knockdown with lower off-target effect, which may be a potentially powerful and safe tool for cancer gene therapy.However, therapeutic effect of current cancer gene therapy that targeting monogene was compromised by the multi-mutational signal pathway alterations of tumorigenesis.Methods: Here, hierarchically tumor-activated nanoCRISPR-Cas13a (CHAIN) is fabricated for multi-pathway-mediated tumor suppression by efficient microRNA disruption in vivo.A fluorinated polyetherimide (PEI; Mw=1.8KD) with graft rate of 33% (PF33) was utilized to compact the CRISPR-Cas13a megaplasmid targeting microRNA-21 (miR-21) (pCas13a-crRNA) via self-assemble to constitute a nanoscale 'core' (PF33/pCas13a-crRNA), which was further wrapped by modified hyaluronan (HA) derivatives (galactopyranoside-PEG2000-HA, GPH) to form CHAIN. Results: The dual-tumor-targeting and tumor-activated CHAIN not only manifested long-term circulation, but augmented tumor cellular uptake and endo/lysosomal escape, thus achieving efficient transfection of CRISPR-Cas13a megaplasmid (~ 13 kb) in tumor cells with minimal toxity.Efficient knockdown of miR-21 by CHAIN restored programmed cell death protein 4 (PDCD4) and reversioninducing-cysteine-rich protein with Kazal motifs (RECK) and further crippled downstream matrix metalloproteinases-2 (MMP-2), which undermined cancer proliferation, migration and invasion.Meanwhile, the miR-21-PDCD4-AP-1 positive feedback loop further functioned as an enhanced force for anti-tumor activity. Conclusion:Treatment with CHAIN in hepatocellular carcinoma mouse model achieved significant inhibition of miR-21 expression and rescued multi-pathway, which triggered substantial tumor growth suppression.By efficient CRISPR-Cas13a induced interference of one oncogenic microRNA, the CHAIN platform exerted promising capabilities in cancer treatment.
KLF5 downregulation desensitizes castration-resistant prostate cancer cells to docetaxel by increasing BECN1 expression and inducing cell autophagy: Erratum
Authors: Jing Jia, Hai-Bao Zhang, Qi Shi, Chao Yang, Jian-Bin Ma, Bin Jin, Xinyang Wang, Dalin He, Peng Guo
Journal: Theranostics (2023)

[This corrects the article DOI: 10.7150/thno.33282.].
Safety of Targeted Axillary Dissection After Neoadjuvant Therapy in Patients With Node-Positive Breast Cancer
Authors: Sherko Kuemmel, Joerg Heil, Simona Bruzas, Elisabeth Breit, Dorothea Schindowski, Hakima Harrach, Ouafaa Chiari, Karin Hellerhoff, Elena Bensmann, Volker Hanf, Sven-Thomas Graßhoff, Petra Deuschle, Kerstin Belke, Silke Polata, Stefan Paepke, Mathias Warm, Johannes Meiler, Christian Schindlbeck, Wencke Ruhwedel, Ulrike Beckmann, Ulrich Groh, Peter Dall, Jens-Uwe Blohmer, Alexander Traut, Mattea Reinisch
Journal: JAMA Surgery (2023)

Importance The increasing use of neoadjuvant systemic therapy (NST) has led to substantial pathological complete response rates in patients with initially node-positive, early breast cancer, thereby questioning the need for axillary lymph node dissection (ALND). Targeted axillary dissection (TAD) is feasible for axillary staging; however, data on oncological safety are scarce. Objective To assess 3-year clinical outcomes in patients with node-positive breast cancer who underwent TAD alone or TAD with ALND. Design, Setting, and Participants The SenTa study is a prospective registry study and was conducted between January 2017 and October 2018. The registry includes 50 study centers in Germany. Patients with clinically node-positive breast cancer underwent clipping of the most suspicious lymph node (LN) before NST. After NST, the marked LNs and sentinel LNs were excised (TAD) followed by ALND according to the clinician’s choice. Patients who did not undergo TAD were excluded. Data analysis was performed in April 2022 after 43 months of follow-up. Exposure TAD alone vs TAD with ALND. Main Outcomes and Measures Three-year clinical outcomes were evaluated. Results Of 199 female patients, the median (IQR) age was 52 (45-60) years. A total of 182 patients (91.5%) had 1 to 3 suspicious LNs; 119 received TAD alone and 80 received TAD with ALND. Unadjusted invasive disease-free survival was 82.4% (95% CI, 71.5-89.4) in the TAD with ALND group and 91.2% (95% CI, 84.2-95.1) in the TAD alone group ( P = .04); axillary recurrence rates were 1.4% (95% CI, 0-54.8) and 1.8% (95% CI, 0-36.4), respectively ( P = .56). Adjusted multivariate Cox regression indicated that TAD alone was not associated with an increased risk of recurrence (hazard ratio [HR], 0.83; 95% CI, 0.34-2.05; P = .69) or death (HR, 1.07; 95% CI, 0.31-3.70; P = .91). Similar results were obtained for 152 patients with clinically node-negative breast cancer after NST (invasive disease-free survival: HR, 1.26; 95% CI, 0.27-5.87; P = .77; overall survival: HR, 0.81; 95% CI, 0.15-3.83; P = .74). Conclusions and Relevance These results suggest that TAD alone in patients with mostly good clinical response to NST and at least 3 TAD LNs may confer survival outcomes and recurrence rates similar to TAD with ALND.
Comparative Effectiveness of Pharmacotherapies for the Risk of Attempted or Completed Suicide Among Persons With Borderline Personality Disorder
Authors: Johannes Lieslehto, Jari Tiihonen, Markku Lähteenvuo, Ellenor Mittendorfer-Rutz, Antti Tanskanen, Heidi Taipale
Journal: JAMA Network Open (2023)

Importance Suicidal behavior is a significant clinical concern in individuals with borderline personality disorder (BPD), but the effectiveness of pharmacotherapy on reducing suicide risk has remained unknown. Objective To study the comparative effectiveness of different pharmacotherapies in preventing attempted or completed suicides in patients with BPD in Sweden. Design, Setting and Participants In this comparative effectiveness research study, nationwide Swedish register databases of inpatient care, specialized outpatient care, sickness absences, and disability pensions were used to identify patients aged 16 to 65 years with registered treatment contact due to BPD during 2006 to 2021. Data were analyzed from September to December 2022. A within-individual design was used, in which each patient was used as their own control to eliminate selection bias. To control protopathic bias, sensitivity analyses were conducted, in which the first 1 or 2 months of medication exposure were omitted from the analyses. Main outcomes and Measures Hazard ratio (HR) for attempted or completed suicide. Results A total of 22 601 patients with BPD (3540 [15.7%] men; mean [SD] age, 29.2 [9.9] years) were included. During the 16-year follow-up (mean [SD] follow-up, 6.9 [5.1] years), 8513 hospitalizations due to attempted suicide and 316 completed suicides were observed. Attention-deficit/hyperactive disorder (ADHD) medication treatment, compared with its nonuse, was associated with a decrease in the risk of attempted or completed suicide (HR, 0.83; 95% CI, 0.73-0.95; false discovery rate [FDR]–corrected P = .001). Treatment with mood stabilizers did not have a statistically significant association with the main outcome (HR, 0.97; 95% CI, 0.87-1.08; FDR-corrected P = .99). Antidepressant (HR, 1.38; 95% CI, 1.25-1.53; FDR-corrected P &amp;amp;lt; .001) and antipsychotic (HR, 1.18; 95% CI, 1.07-1.30; FDR-corrected P &amp;amp;lt; .001) treatments were associated with an elevated risk of attempted or completed suicide. Of the investigated pharmacotherapies, treatment with benzodiazepines was associated with the highest risk of attempted or completed suicide (HR, 1.61; 95% CI, 1.45-1.78; FDR-corrected P &amp;amp;lt; .001). These results remained similar when controlling for potential protopathic bias. Conclusions and Relevance In this comparative effectiveness research study of a Swedish nationwide cohort, ADHD medication was the only pharmacological treatment associated with reduced risk of suicidal behavior among patients with BPD. Conversely, the findings suggest that benzodiazepines should be used with care among patients with BPD due to their association with increased risk of suicide.
Upstream open reading frame-encoded MP31 disrupts the mitochondrial quality control process and inhibits tumorigenesis in glioblastoma
Authors: Nunu Huang, Zhipeng Chen, Xuesong Yang, Yixin Gao, Jian Zhong, Yan Li, Feizhe Xiao, Xiuxing Wang, Yu Shi, Nu Zhang
Journal: Neuro-Oncology (2023)

Abstract Background Mitochondrial hyperpolarization achieved by the elevation of mitochondrial quality control (MQC) activity is a hallmark of glioblastoma (GBM). Therefore, targeting the MQC process to disrupt mitochondrial homeostasis should be a promising approach for GBM therapy. Methods We used 2-photon fluorescence microscopy, Fluorescence-Activated Cell Sorting, and confocal microscopy with specific fluorescent dyes to detect the mitochondrial membrane potential (MMP) and mitochondrial structures. Mitophagic flux was measured with mKeima. Results MP31, a phosphatase and tensin homolog (PTEN) uORF-translated and mitochondria-localized micropeptide, disrupted the MQC process and inhibited GBM tumorigenesis. Re-expression of MP31 in patient-derived GBM cells induced MMP loss to trigger mitochondrial fission but blocked mitophagic flux, leading to the accumulation of damaged mitochondria in cells, followed by reactive oxygen species production and DNA damage. Mechanistically, MP31 inhibited lysosome function and blocked lysosome fusion with mitophagosomes by competing with V-ATPase A1 for lactate dehydrogenase B (LDHB) binding to induce lysosomal alkalinization. Furthermore, MP31 enhanced the sensitivity of GBM cells to TMZ by suppressing protective mitophay in vitro and in vivo, but showed no side effects on normal human astrocytes or microglia cells (MG). Conclusions MP31 disrupts cancerous mitochondrial homeostasis and sensitizes GBM cells to current chemotherapy, without inducing toxicity in normal human astrocytes and MG. MP31 is a promising candidate for GBM treatment.
Decline in New HIV Cases Projected to Fall Short of US Goals
Authors: Emily Harris
Journal: JAMA (2023)

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